Adherence to antiviral therapy is a significant issue for HIV-infected drug abusers. The combined studies of lenfivirus-infected rodent and rhesus macaques proposed here build upon exciting preliminary data obtained on nanoformulafions of anfiretrovirals (nanoART) and the data that will result from projects 1 and 2 (A. Kabanov and H. Gendelman). Before proceeding to nonhuman primate studies, rodent testing of nanoART in virus-infected EcoHIV and/or humanized mice. These studies will be conducted with D. Volsky and L. Poluektova. Thus, we will begin in Aim 1 performing rodent biodistribufion (including bioimaging) and pharmacokinefic (PK) tesfing (years 1 and 2, using cores B and C, M. Boska and C. Fletcher) in infected animals as a first pass screen for antiretroviral efficacy and tissue toxicities in vivo (oversight and biostafisfician support through core A, H. Gendelman). We will then proceed in specific aim 2 for PK, drug tissue distribufion, and safety studies in uninfected nonhuman primates (year 3), and then in specific aim 3 perform nanoART evaluafions in SHIV-infected monkeys, including PK, imaging, and efficacy studies, with extensive tissue analyses (years 3-5). These studies will predict whether long-spaced dosing protocols would yield acceptable drug plasma levels in monkeys and whether such developed protocols are efficacious against virus in primates. In toto, studies in the SHIV/rhesus monkey model will yield important information immediately applicable to future human clinical trials. The wealth of data, from pharmacokinefics, organ distribufion, effects on the virus, immune and other physiological systems are crucial pre-clinical steps in the development ofthis excifing therapeufic development.